Aerosol-forming porous membrane with certain pore structure

ABSTRACT

A nozzle comprised of a thin, flexible membrane material having a plurality of pores is disclosed. In one embodiment, the pores have an unflexed exit aperture diameter in the range of about 0.5 to about 2 microns (preferably about 1 micron) and are positioned substantially uniformly in the material, preferably about 50 microns apart. The nozzle preferably has a conical or trumpet-shaped cross-section. In another aspect of the invention, the exit aperture of the nozzle is surrounded by an elevated area protruding above the substantially planar exit side of the membrane in order to prevent intrusion of liquid back into the nozzle. The nozzle can be used to form an aerosol containing a pharmaceutical composition from the exit side of the nozzle upon forcible application of the composition to the entrance side of the nozzle. This aerosol can be used to administer the pharmaceutical composition, for example, to the eye or to a selected portion of the respiratory tract. The nozzle is preferably a component of a container which holds a formulation of drug.

BACKGROUND OF THE INVENTION

Aerosol therapy can be accomplished by aerosolization of a formulation(e.g., a drug formulation or diagnostic agent formulation) andinhalation of the aerosol. The formulation can be used to treat lungtissue locally and/or be absorbed into the circulatory system to deliverthe drug systemically. Where the formulation contains a diagnosticagent, the formulation can be used for diagnosis of, for example,conditions and diseases associated with pulmonary dysfunction. Ingeneral, aerosolized particles for respiratory delivery must have adiameter of 12 microns or less. However, the preferred particle sizevaries with the site targeted (e.g, delivery targeted to the bronchi,bronchia, bronchioles, alveoli, or circulatory system). For example,topical lung treatment can be accomplished with particles having adiameter in the range of 0.01 to 12.0 microns. Effective systemictreatment requires particles having a smaller diameter, generally in therange of 0.5 to 6.0 microns, while effective ocular treatment isadequate with particles having a larger diameter, generally 15 micronsor greater, generally in the range of 15-100 microns.

Generation of aerosolized particles and their respiratory delivery isgenerally accomplished by three distinct methodologies. One method usesa device known as a "metered dose inhaler" (MDI). Drugs delivered usingan MDI are dispersed in a low boiling point propellant (e.g., achlorofluorocarbon or hydrofluorocarbon) and loaded in a pressurizedcanister. A metered amount of the drug/propellant formulation isreleased from the MDI by activating a valve on the canister. Thepropellant "flashes" or quickly evaporates and particles of the drug areinhaled by the patient. Although MDIs provide a self-contained, easilyportable device, the propellants have adverse environmental effects. Inaddition, it is difficult to reliably deliver a precise dosage of drugusing an MDI. The patient frequently actuates the device at theincorrect point during the breathing cycle, or breathes at the wrongflow rate while inhaling the drug. Thus, patients may receiveinconsistent doses, sometimes inspiring too little medication, othertimes taking a second dose after a partial failure and thereby receivingtoo much medication.

Breath actuated drug delivery devices, which attempt to overcome thedosing problems of MDIs, are activated to release a dose when thepatient's inspiratory flow crosses a fixed threshold. However, thepatient's inspiratory effort may not be sufficient to satisfy thethreshold to trigger drug release. Or, although the patient'sinspiration effort may be sufficient to release a metered dose, theinspired volume following the release may not be sufficient to cause theaerosol medication to pass into the desired portion of the patient'sairways. Finally, whether breath-actuated or not, MDIs generate anaerosol that can contain particles of very different sizes. Largerparticles are not delivered to the same site in the lung and/or at thesame rate as the smaller particles in the aerosol. The production of anaerosol of varying particle size thus makes the delivery of a precise,reproducible dosage of medication or diagnostic agent to the desiredregions of the respiratory tract extremely difficult if not impossible.

The second method for generation of aerosolized particles forrespiratory delivery uses devices known as "dry powder inhalers" (DPI).DPIs typically use bursts of air to entrain small amounts of the drug,thus forming a dust cloud of dry drug particles. DPIs do not require thepropellants of MNDIs. However, like MDIs, DPIs form aerosols composed ofmany different sizes of particles, making the delivery of a precise doseto a desired site in the respiratory tract difficult.

Nebulizers, devices used in a third method of respiratory drug delivery,utilize various means to create a fog or mist from an aqueous solutionor suspension containing a pharmaceutically active drug. The mistcreated by the nebulizer device is directed towards the face of thepatient and inhaled through the mouth and/or nose. The formulationdelivered with nebulizers is sometimes diluted prior to delivery. Theentire diluted formulation must generally be administered within asingle dosing event in order to maintain the desired level of sterility.

Nebulizer devices can be quite useful when the precise dosing of thedrug being delivered to the patient is not of particular importance,e.g., for treatment of a patient with a bronchodilator until he feelssome improvement in lung function. When precise dosing is moreimportant, the nebulizer device and delivery methodology suffers frommany of the disadvantages of metered dose inhaler devices andmethodology as described above. In addition, nebulizers generally arelarge and not easily transportable devices. Accordingly, a nebulizer canonly be used within a fixed location such as the patient's home, thedoctor's office and/or hospital. Yet another disadvantage of nebulizersis that they produce an aerosol which has a distribution of particlesizes, not all of which are of appropriate size to reach the targetedareas of the lung.

An aerosolization device can also be used to deliver treatment to theeye. Ophthalmic treatment fluids are commonly administered to the eye bymeans of eye drops or ointments. The use of eye drops has a number ofdisadvantages, primarily as a consequence of the difficulty with whichdrops are accepted by the patient. The drops are relatively large, andthe instinctive blink that is provoked by the arrival of a drop on theeye severely limits the amount or proportion of fluid that actuallycontacts the target area of the eye. Typically less than 10% of a 50 μldrop reaches the desired site of administration, the remainder beinglost by drainage, either externally or through nasolacrimal drainage.Such use of expensive treatment fluids leads to substantial uncertaintyregarding the effectiveness of treatment. Ointments are associated withsimilar problems in their use to accomplish ocular therapy.

Various techniques for delivering treatment fluid to the eye are known.Most employ treatment systems in which treatment fluid is drawn from areservoir and discharged in a controlled manner to the eye (see, e.g.,WO96/06581). U.S. Pat. No. 3,934,585 disclosed a variety of mechanismsfor delivering unit doses of treatment fluid to the human eye. Forexample, treatment fluid can be delivered by applying compressed air toone end of a tube resulting in the discharge of treatment fluid from theother end.

Devices and methods for controlling aerosol particle size are known inthe art. For example, U.S. Pat. No. 4,926,852 described control ofparticle size by metering a dose of medication into a flow-throughchamber that has orifices to limit the flow rate. U.S. Pat. No.4,677,975 described a nebulizer device having baffles to removeparticles above a selected size from an aerosol. U.S. Pat. No. 3,658,059employed a baffle that changes the size of an aperture in the passage ofthe suspension being inhaled to select the quantity and size ofsuspended particles delivered. U.S. Pat. No. 5,497,944 described amethod and device for generating an aerosol by passing the formulationthrough a small nozzle aperture at high pressure. However, devices thatprocess the aerosol particle size after generation (e.g., by filteringthe aerosol after it is formed from the formulation) are typicallyinefficient, wasteful, and/or require a substantially greater amount offorce to generate the aerosol.

Co-owned U.S. Pat. No. 5,544,646 and U.S. patent applications Ser. Nos.08/454,421, 08/630,391, 08/693,593 and 08/804,041 describe devices andmethods useful in the generation of aerosols suitable for drug delivery.A drug formulation is forcibly applied to one side of thepore-containing membrane so as to produce an aerosol on the exit side ofthe membrane. Aerosols containing particles with a more uniform sizedistribution can be generated using such devices and methods, and can bedelivered to particular locations within the respiratory tract.

One impediment to aerosol formation using prior membranes is theaccumulation of a liquid layer on the exit side of the membrane. Thiscan occur when forcible application of the formulation to the entranceside of the nozzle, rather than causing aerosolization, causes lateralspreading of liquid from the exit side, for example from poorly formedor irregular pores, or where the pressure is insufficient toconsistently generate an aerosol. This liquid layer can spread toproperly functioning pores and thereby disrupt their function, furtherdegrading performance of the nozzle. This problem is particularly acute,for example, where the pores are closely or irregularly spaced, or whereextrusion takes place over a significant period of time, or when thenozzle is to be used for repeated administration.

SUMMARY OF THE INVENTION

We have now invented an extrusion nozzle that is particularly wellsuited to extrusion of a formulation into the entraining airstream anddelivery of particles having an improved size distribution to therespiratory tract. The nozzles of the invention maximize the conversionof pressure on the formulation container to kinetic energy of theformulation being extruded, and provide aerosol particles of the desiredsizes.

One aspect of the invention is a nozzle for aerosolizing a formulation,said nozzle comprising a membrane having about 200 to about 1,000 holes,said holes having an average relaxed exit aperture diameter of fromabout 0.5 to about 1.5 μm and spaced from about 30 to about 70 μm apartfrom each other. The membrane is preferably flexible.

In a further aspect of the invention, a nozzle is provided wherein thearea surrounding the exit aperture of the pores is elevated above the(otherwise substantially planar) exit side of the film so as to preventintrusion of liquid into the exit aperture of the pores.

In another aspect of the invention, a nozzle is provided wherein theexit aperture of the pores has a smaller diameter than the entranceaperture.

In yet another aspect of the invention, a nozzle is provided wherein thepores are incompletely formed so that, upon administration of pressureto the entrance side of the film, the exit aperture is formed bybursting outward the exit side of the pores, thereby forming an elevatedarea preventing liquid intrusion into the exit aperture.

In a further aspect of the invention, a strip containing multiplenozzles is provided.

Another aspect of the invention is a method for aerosolizing aformulation in a way that maximizes the amount of formulation availablefor inhalation, comprising extruding the formulation into an airstreamthrough a flexible, porous membrane, where the pores are from about 0.5to about 1.5 microns in exit aperture diameter when unflexed, and arespaced about 30-70 μm apart.

Still another aspect of the invention is a method for aerosolizing aformulation through a nozzle comprising such pores where the areasurrounding the exit aperture of the pores is elevated above thesubstantially planar exit side of the membrane.

Yet another aspect of the invention is a method for aerosolizing aformulation through pores having entrance apertures wider than theirexit apertures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic drawing of an excimer laser apparatus used toablate pores in a material using the method of the invention.

FIG. 2 is a cross-sectional view of a preferred embodiment of acontainer used in carrying out the invention, showing elevated areassurrounding the exit apertures of the nozzle pores.

FIG. 3 is a cross-sectional view of a container of a preferredembodiment of a container used in carrying out the invention.

FIG. 4 is a top plan view of a disposable package of the invention.

FIG. 5 is a cross-sectional view of a portion of a disposable package ofthe invention.

FIG. 6 is a cross-sectional view of the container of FIG. 2 in use in achannel of an aerosol delivery device.

FIG. 7 is a cross-sectional view of an aerosol delivery device of theinvention having a multidose container and a ribbon of low resistancefilters and a ribbon of porous membranes.

FIG. 8 is a cross-sectional view of an aerosol delivery device of theinvention having a multidose container and single ribbon having bothinterconnected low resistance filters and nozzles comprised of porousmembranes.

FIG. 9 is a cross-sectional view of an aerosol delivery device of theinvention.

FIG. 10 is a cross-sectional view of an aerosol delivery device of theinvention loaded with a cassette.

FIG. 11 is a scanning electron micrograph of the exit aperture of a poreformed by the methodology of the present invention so as to have anelevated area surrounding the exit aperture to prevent intrusion of theformulation back into the pore.

FIG. 12 is a graph of the aerosol quality vs. pore size for porousmembranes generated by the method of the present invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Before the present methods of generating an aerosol and delivering anaerosolized formulation to a patient and devices, containers, andformulations used in connection with such are described, it is to beunderstood that this invention is not limited to the particularmethodology, devices, containers and formulations described, as suchmethods, devices, containers and formulations may, of course, vary. Itis also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto limit the scope of the present invention which will be limited onlyby the appended claims.

It must be noted that as used herein and in the appended claims, thesingular forms "a," "an," and "the" include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to "aformulation" includes mixtures of different formulations, reference to"an asthma attack" includes one or more of such events, and reference to"the method of treatment" and to "the method of diagnosis" includesreference to equivalent steps and methods known to those skilled in theart, and so forth.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimits of that range is also specifically disclosed. Each smaller rangebetween any stated value or intervening value in a stated range and anyother stated or intervening value in that stated range is encompassedwithin the invention. The upper and lower limits of these smaller rangesmay independently be included or excluded in the range, and each rangewhere either, neither or both limits are included in the smaller rangeis also encompassed within the invention, subject to any specificallyexcluded limit in the stated range. Where the stated range includes oneor both of the limits, ranges excluding either or both of those includedlimits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the invention, the preferred methods andmaterials are now described. All publications mentioned herein areincorporated herein by reference to describe and disclose specificinformation for which the reference was cited.

The publications discussed above are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the invention is notentitled to antedate such disclosure by virtue of prior invention.

DEFINITIONS

The terms "package" and "disposable package" are used interchangeablyherein and shall be interpreted to mean a container or two or morecontainers linked together by an interconnecting means wherein eachcontainer preferably includes one or more channels which provide forfluid connection from the container to a nozzle comprised of a porousmembrane, which nozzle is preferably not positioned directly over thecontainer, and wherein each container includes at least one surface thatis collapsible in a manner so as to allow the forced displacement of thecontents of the container through a low resistance filter and out thenozzle (without rupturing the container) in a manner such that thecontents are aerosolized. There are at least two variations of thepackage, depending on whether the drug can be stably stored in a liquidform or must be stored dry and combined with liquid immediately prior toaerosolization.

The contents of each container preferably comprises a formulation,preferably a flowable formulation, more preferably a liquid, flowableformulation, which includes a pharmaceutically active drug or adiagnostic agent. If the drug or diagnostic agent is not liquid and of asufficiently low viscosity to allow the drug to be aerosolized, the drugor diagnostic agent is dissolved or dispersed in an excipient carrier,preferably without any additional material such as preservatives thatmight affect the patient. When the contents must be stored in a drystate, the package further includes another container that holds theliquid and can be combined with the dry drug immediately prior toadministration.

The term "container" is used herein to mean a receptacle for holdingand/or storing a drug formulation. The container can be single-dose ormultidose, and/or disposable or refillable.

The term "cassette" shall be interpreted to mean a container whichholds, in a protective cover, a package or a plurality of packages whichpackages are interconnected to each other and held in the cassette in anorganized manner, e.g., interfolding or wound. The cassette isconnectable to a dispensing device, which dispensing device may includea power source, e.g., one or more batteries which provide power to thedispensing device.

The term "porosity" is used herein to mean a percentage of an area of asurface area that is composed of open space, e.g., a pore, hole, channelor other opening, in a membrane, nozzle, filter or other material. Thepercent porosity is thus defined as the total area of open space dividedby the area of the material, expressed as a percentage (multiplied by100). High porosity (e.g., a porosity greater than 50%) is associatedwith high flow rates per unit area and low flow resistance. In general,the porosity of the nozzle is less than 10%, and can vary from 10⁻³ % to10%, while the porosity of the filter is at least 1%, and preferably itis at least 50% porous.

The term "porous membrane" shall be interpreted to mean a membrane ofmaterial having any given outer parameter shape, but preferably having aconvex shape, wherein the membrane has a plurality of pores therein,which openings may be placed in a regular or irregular pattern, andwhich pores have an unflexed diameter of their exit aperture in therange of 0.25 micron to 6 microns and a pore density in the range of 1to 1,000 pores per square millimeter for respiratory delivery. Forocular delivery, the pores have an unflexed diameter of their exitaperture in the range of 5 microns to 50 microns, preferably 7.5 to 25microns, and a similar pore density. The porous membrane has a porosityof about 0.0005% to 0.2%, preferably about 0.01% to 0.1%. In oneembodiment, the porous membrane comprises a single row of pores on,e.g., a large piece of membrane material. The pores may be planar withrespect to the surface of the porous membrane material, or may have aconical configuration. The membrane material is preferably hydrophobicand includes materials such as polycarbonates, polyimides, polyethers,polyether imides, polyethylene and polyesters which may have the poresformed therein by any suitable method including laser drilling oranisotropic etching through a thin film of metal or other suitablematerial. The membrane preferably has sufficient structural integrity sothat it is maintained intact (will not rupture) when subjected to forcein the amount up to about 40 bar, preferably of up to about 50 bar whilethe formulation is forced through the pores.

The term "low resistance filter" shall be interpreted to mean a filterof material having any given outer parameter shape, and having aplurality of openings therein, which openings may be placed in a regularor irregular pattern. The openings in the filter can be of any shape,and are preferably substantially evenly distributed throughout thefilter surface area. Preferably, the porosity of the low resistancefilter is greater than 50%, preferably at least 60%, more preferably atleast 70%. Preferably, the low resistance filter prevents passage ofparticles greater than about 0.5 microns in size (e.g., having adiameter greater than 0.5 microns). Where the filter openings are pores,the pores can have a diameter in the range of from about 0.25 micron to6 microns for respiratory tract delivery, or from about 5 microns to 50microns for ocular delivery. The filter has an opening density in therange of from about 10 to 20,000,000 openings per mm². Preferably thefilter has holes of about 0.5 μm positioned about 0.5 μm apart at adensity of 10⁶ holes per mm². Preferably, the ratio of the pore densityof the porous membrane to the low resistance filter is in the range ofabout 1:1.5 to about 1:100,000; the ratio of the pore diameter of thepores of the porous membrane to the diameter of the openings of the lowresistance filter is in the range of from about 1:0.95 to 1:0.1.Preferably, the flow resistance of the filter is the same as or lowerthan the flow resistance of the porous membrane used in conjunction withthe filter. The filter is preferably comprised of a material having adensity in the range of 0.25 to 3.0 mg/cm², more preferably 1.7 mg/cm²,and a thickness of about 10 microns to about 500 microns, morepreferably about 20 to 150 microns. The filter can be made of anymaterial suitable for use in the invention, e.g., cellulose ester, mixedcellulose ester, modified polyvinylidene fluoride,polytetrafluoroethylene, bisphen polycarbonate, borosilicate glass,silver, polypropylene, polyester, polyimide, polyether, or any suitablepolymeric material. The filter material includes materials such aspolycarbonates and polyesters which may have the pores formed therein byany suitable method, including anisotropic etching or by etching througha thin film of metal or other suitable material, electron dischargemachining, or laser micromachining. The filter preferably has sufficientstructural integrity such that it is maintained intact (i.e., will notrupture) when subjected to force up to about 40 bar, preferably up toabout 50 bar during extrusion of the formulation through the pores (offilter or membrane). The porosity of the low resistance filter is 5-85%,preferably 70%, while the porosity of the nozzle is 10⁻⁴ %-1%,preferably 0.001%-0.1%.

The term "flow resistance" shall be interpreted to mean the resistanceassociated with the passage of a liquid or aerosol through a porousmaterial, e.g., through the porous membrane or the low resistance filterdescribed herein. Flow resistance is affected by the size and density ofpores in the porous material, the viscosity of a liquid passing throughthe material, and other factors well known in the art. In general, "lowresistance" of the "low resistance filter" means that the flowresistance of the low resistance filter is substantially the same as orless than the flow resistance of the porous membrane used in conjunctionwith the low resistance filter.

The terms "drug", "active agent", "pharmaceutically active drug" and thelike are used interchangeably herein to encompass compounds which areadministered to a patient in order to obtain a desired pharmacologicaleffect. The effect may be a local or topical effect in the eye orrespiratory tract such as in the case of most respiratory or ophthalmicdrugs or may be systemic as with analgesics, narcotics, hormones,hematopoietic drugs, various types of peptides including insulin andhormones such as EPO. Other exemplary drugs are set forth in U.S. Pat.No. 5,419,315, issued May 30, 1995, PCT Published Application WO96/13291, published May 9, 1996, and PCT Published Application WO96/13290, published May 9, 1996, incorporated herein by reference.

The term "respiratory drug" shall be interpreted to mean anypharmaceutically effective compound used in the treatment of anyrespiratory disease and in particular the treatment of diseases such asasthma, bronchitis, emphysema and cystic fibrosis. Useful "respiratorydrugs" include those which are listed within the Physician's DeskReference (most recent edition). Such drugs include beta adrenergicagonists which include bronchodilators including albuterol,isoproterenol sulfate, metaproterenol sulfate, terbutaline sulfate,pirbuterol acetate, salmeterol xinotoate, formoteorol; steroidsincluding corticosteroids used as an adjunct to beta agonistbronchodilators such as beclomethasone dipropionate, flunisolide,fluticasone, budesonide and triamcinolone acetonide; antibioticsincluding antifungal and antibacterial agents such as chloramphenicol,chlortetracycline, ciprofloxacin, framycetin, fusidic acid, gentamicin,neomycin, norfloxacin, ofloxacin, polymyxin, propamidine, tetracycline,tobramycin, quinolines, and the like; and also includes peptidenonadrenergic noncholinergic neurotransmitters and anticholinergics.Antiinflammatory drugs used in connection with the treatment ofrespiratory diseases include steroids such as beclomethasonedipropionate, triamcinolone acetonide, flunisolide and fluticasone.Other antuinflammatory drugs and antiasthmatics which includecromoglycates such as cromolyn sodium. Other respiratory drugs whichwould qualify as bronchodilators include anticholinergics includingipratropium bromide. Other useful respiratory drugs include leukotriene(LT) inhibitors, vasoactive intestinal peptide (VIP), tachykininantagonists, bradykinin antagonists, endothelin antagonists, heparinfurosemide, antiadhesion molecules, cytokine modulators, biologicallyactive endonucleases, recombinant human (rh) DNase, α₁ antitrypsin andantibiotics such as gentamicin, tobramycin, cephalosporins orpenicillins, nucleic acids and gene vectors. The present invention isintended to encompass the free acids, free bases, salts, amines andvarious hydrate forms including semihydrate forms of such respiratorydrugs and is particularly directed towards pharmaceutically acceptableformulations of such drugs which are formulated in combination withpharmaceutically acceptable excipient materials generally known to thoseskilled in the art--preferably without other additives such aspreservatives. Preferred drug formulations do not include additionalcomponents such as preservatives which have a significant effect on theoverall formulation. Thus preferred formulations consist essentially ofpharmaceutically active drug and a pharmaceutically acceptable carrier(e.g., water and/or ethanol). However, if a drug is liquid without anexcipient the formulation may consist essentially of the drug providedthat it has a sufficiently low viscosity that it can be aerosolizedusing a dispenser of the present invention.

The term "ophthalmic drug" or "ophthalmic treatment fluid" refers to anypharmaceutically active compound used in the treatment of any oculardisease. Therapeutically useful compounds include, but are not limitedto, (1) antiglaucoma compounds and/or compounds that decreaseintraocular pressure such as β-adrenoceptor antagonists (e.g.,cetamolol, betaxolol, levobunolol, metipranolol, timolol, etc.),mitotics (e.g., pilocarpine, carbachol, physostigmine, etc.),sympatomimetics (e.g., adrenaline, dipivefrine, etc.), carbonicanhydrase inhibitors (e.g., acetazolamide, dorzolamide, etc.),prostaglandins (e.g., PGF-2 alpha), (2) antimicrobial compoundsincluding antibacterial and antifungal compounds (e.g., chloramphenicol,chlortetracycline, ciprofloxacin, framycetin, fusidic acid, gentamicin,neomycin, norfloxacin, ofloxacin, polymyxin, propamidine, tetracycline,tobramycin, quinolines, etc.), (3) antiviral compounds (e.g., acyclovir,cidofovir, idoxuridine, interferons, etc.), (4) aldose reductaseinhibitors (e.g., tolrestat, etc.), (5) antiinflammatory and/orantiallergy compounds (e.g., steroidal compounds such as betamethasone,clobetasone, dexamethasone, fluorometholone, hydrocortisone,prednisolone, etc. and nonsteroidal compounds such as antazoline,bromfenac, diclofenac, indomethacin, lodxamide, saprofen, sodiumcromoglycate, etc., (6) artificial tear/dry eye therapies, comfortdrops, irrigation fluids, etc. (e.g., physiological saline, water, oroils; all optionally containing polymeric compounds such asacetylcysteine, hydroxyethylcellulose, hydroxymellose, hyaluronic acid,polyvinyl alcohol, polyacrylic acid derivatives, etc.), (7) localanaesthetic compounds (e.g., amethocaine, lignocaine, oxbuprocaine,proxymetacaine, etc.), (8) compounds which assist in the healing ofcorneal surface defects (e.g., cyclosporine, diclofenac, urogastrone andgrowth factors such as epidermal growth factor), (9) mydriatics andcycloplegics (e.g., atropine, cyclopentolate, homatropine, hyoscine,tropicamide, etc.), (10) compounds for the treatment of pterygium (e.g.,mitomycin C., collagenase inhibitors such as batimastat, etc.), (11)compounds for the treatment of macular degeneration and/or diabeticretinopathy and/or cataract prevention, (12) compounds for systemiceffects following absorption into the bloodstream after ocularadministration (e.g., insulin, narcotics, analgesics, anesthetics).

The terms "diagnostic" and "diagnostic agent" and the like are usedinterchangeably herein to describe any compound that is delivered to apatient in order to carry out a diagnostic test or assay on the patient.Such agents are often tagged with a radioactive or fluorescent componentor other component which can be readily detected when administered tothe patient. Exemplary diagnostic agents include, but are not limitedto, methacholine, histamine, salt, specific allergens (such as pollen orpollen extracts), sulphites, and imaging agents for magnetic resonanceimaging and/or scintigraphy. Diagnostic agents can be used to, forexample, assess bronchial constriction in patients having or suspectedof having cystic fibrosis or asthma. Radiolabelled aerosols can be usedto diagnose pulmonary embolism, or to assess mucociliary clearance invarious chronic obstructive diseases of the lung. Diagnostic agents canalso be used to assess ophthalmic conditions. Exemplary oculardiagnostic agents include, but are not limited to, such compounds asfluorescein or rose bengal.

The term "formulation" is intended to encompass any drug or diagnosticagent formulation which is delivered to a patient using the presentinvention. Such formulations generally include the drug or diagnosticagent present within a pharmaceutically acceptable inert carrier. Theformulation is generally in a liquid flowable form which can be readilyaerosolized, the particles having a particle size in the range of 0.5 to12 microns in diameter for respiratory administration. Formulations canbe administered to the patient using device of the invention can beadministered by nasal, intrapulmonary, or ocular delivery.

The terms "aerosol," "aerosolized formulation," and the like, are usedinterchangeably herein to describe a volume of air which has suspendedwithin it particles of a formulation comprising a drug or diagnosticagent wherein the particles have a diameter in the range of 0.5 to 12microns, for respiratory therapy, or in the range of 15 to 50 micronsfor ocular therapy.

The term "aerosol-free air" is used to describe a volume of air which issubstantially free of other material and, in particular, substantiallyfree of particles of respiratory drug.

The term "dosing event" shall be interpreted to mean the administrationof drug or diagnostic agent to a patient by the ocular or respiratory(e.g., nasal or intrapulmonary) route of administration (i.e.,application of a formulation to the patient's eye or to the patient'srespiratory tract by inhalation of aerosolized particles) which eventmay encompass one or more releases of drug or diagnostic agentformulation from a dispensing device over a period of time of 15 minutesor less, preferably 10 minutes or less, and more preferably 5 minutes orless, during which period multiple administrations (e.g., applicationsto the eye or inhalations) may be made by the patient and multiple dosesof drug or diagnostic agent may be released and administered. A dosingevent shall involve the administration of drug or diagnostic formulationto the patient in an amount of about 10 μl to about 1,000 μl in a singledosing event. Depending on the drug concentration in the formulation, asingle package may not contain sufficient drug for therapy or diagnosis.Accordingly, a dosing event may include the release of drug ordiagnostic agent contained from several containers of a package held ina cassette or the drug or diagnostic agent contained within a pluralityof such containers when the containers are administered over a period oftime, e.g., within 5 to 10 minutes of each other, preferably within 1-2minutes of each other.

The term "velocity of the drug" or "velocity of particles" shall meanthe average speed of particles of drug or diagnostic agent formulationmoving from a release point such as the porous membrane of the nozzle ora valve to a patient's mouth or eye. In a preferred embodimentpertaining to respiratory therapy, the relative velocity of theparticles is zero or substantially zero with reference to the flowcreated by patient inhalation.

The term "bulk flow rate" shall mean the average velocity at which airmoves through a channel.

The term "flow boundary layer" shall mean a set of points defining alayer above the inner surface of a channel through which air flowswherein the air flow rate below the boundary layer is substantiallybelow the bulk flow rate, e.g., 50% or less than the bulk flow rate.

The term "carrier" shall mean a flowable, pharmaceutically acceptableexcipient material, preferably a liquid, flowable material, in which adrug or diagnostic agent is suspended in or more preferably dissolvedin. Useful carriers do not adversely interact with the drug ordiagnostic agent and have properties which allow for the formation ofaerosolized particles, which particles preferably have a diameter in therange of 0.5 to 12.0 microns that are generated by forcing a formulationcomprising the carrier and drug or diagnostic agent through pores havingan unflexed diameter of 0.25 to 6.0 microns for delivery to therespiratory tract. Similarly, a useful carrier for delivery to the eyedoes not adversely interact with the drug or diagnostic agent and hasproperties which allow for the formation of aerosolized particles, whichparticles preferably have a diameter of 15 to 50 microns and aregenerated by forcing the formulation comprising the carrier and drug ordiagnostic agent through pores 7.5 to 25 microns in relaxed diameter.Preferred carriers include water, ethanol, saline solutions and mixturesthereof, with pure water being preferred. Other carriers can be usedprovided that they can be formulated to create a suitable aerosol and donot adversely affect human tissue or the drug or diagnostic agent to bedelivered.

The term "measuring" describes an event whereby the (1) total lungcapacity, (2) inspiratory flow rate or (3) inspiratory volume of thepatient is measured and/or calculated and the information used in orderto determine an optimal point in the inspiratory cycle at which torelease an aerosolized and/or aerosol-free volume of air. An actualmeasurement of both rate and volume may be made or the rate can bedirectly measured and the volume calculated based on the measured rate.The total lung capacity can be measured or calculated based on thepatient's height, sex and age. It is also preferable to continuemeasuring inspiratory flow during and after any drug delivery and torecord inspiratory flow rate and volume before, during and after therelease of drug. Such reading makes it possible to determine if drug ordiagnostic agent was properly delivered to the patient.

The term "monitoring" shall mean measuring lung functions such asinspiratory flow, inspiratory flow rate, and/or inspiratory volume sothat a patient's lung function as defined herein, can be evaluatedbefore and/or after drug delivery thereby making it possible to evaluatethe effect of drug delivery on, for example, the patient's lungfunction.

The term "inspiratory flow profile" shall be interpreted to mean datacalculated in one or more events measuring inspiratory flow andcumulative volume, which profile can be used to determine a point withina patient's inspiratory cycle which is optimal for the release of drugto be delivered to a patient. An optimal point within the inspiratorycycle for the release of an aerosol volume is based, in part, on (1) apoint most likely to deliver the aerosol volume to a particular area ofa patient's respiratory tract, in part on (2) a point within theinspiratory cycle likely to result in the maximum delivery of drug and,in part, on (3) a point in the cycle most likely to result in thedelivery of a reproducible amount of drug to the patient at each releaseof drug. The criteria 1-3 are listed in a preferred order of importance.However, the order of importance can change based on circumstances. Thearea of the respiratory tract being treated is determined by adjustingthe volume of aerosol-containing or aerosol-free air and/or by adjustingthe particle size of the aerosol. The repeatability is determined byreleasing at the same point in the respiratory cycle each time drug isreleased. To provide for greater efficiency in delivery, the drugdelivery point is selected within given parameters.

The terms "formulation" and "flowable formulation" and the like are usedinterchangeably herein to describe any pharmaceutically active drug(e.g., a respiratory drug, or drug that acts locally or systemically,and that is suitable for respiratory delivery) or diagnostic agentcombined with a pharmaceutically acceptable carrier in flowable formhaving properties such that it can be aerosolized to particles having adiameter of 0.5 to 12.0 microns for respiratory therapy, or 15 to 75microns for ocular therapy. Such formulations are preferably solutions,e.g., aqueous solutions, ethanolic solutions, aqueous/ethanolicsolutions, saline solutions, colloidal suspensions and microcrystallinesuspensions. Preferred formulations are drug(s) and/or diagnosticagent(s) dissolved in a liquid, preferably in water.

The term "substantially dry" shall mean that particles of formulationinclude an amount of carrier (e.g., water or ethanol) which is equal to(in weight) or less than the amount of drug or diagnostic agent in theparticle, more preferably it means free water is not present.

The terms "aerosolized particles" and "aerosolized particles offormulation" shall mean particles of formulation comprised of carrierand drug and/or diagnostic agent that are formed upon forcing theformulation through a nozzle, which nozzle comprises a flexible porousmembrane. Where respiratory therapy is desired, the particles are of asufficiently small size such that when the particles are formed, theyremain suspended in the air for a sufficient amount of time forinhalation by the patient through his nose or mouth. Where oculartherapy is desired, the particles formed are of a size optimal forapplication to the eye. Preferably, particles for respiratory deliveryhave a diameter of from about 0.5 micron to about 12 microns, and aregenerated by forcing the formulation through the pores of a flexibleporous membrane, where the pores have an unflexed exit aperture diameterin the range of about 0.25 micron to about 6.0 microns. More preferably,the particles for respiratory delivery have a diameter of about 1.0 to8.0 microns with the particles created by being moved through poreshaving an unflexed exit aperture diameter of about 0.5 to about 4microns. For ocular delivery, the particles have a diameter from about15 micron to about 75 microns, and are generated by forcing theformulation through the pores of a flexible porous membrane, where thepores have an unflexed exit aperture diameter in the range of about 5micron to about 50 microns. More preferably, the particles for oculardelivery have a diameter of about 15 to 50 microns, and can be generatedby forcing the formulation through flexible membrane pores having anunflexed exit aperture diameter of about 7.5 to about 25 microns. Ineither respiratory or ocular delivery, the flexible membrane pores arepresent at about 10 to 10,000 pores over an area in size of from about 1sq. millimeter to about 1 sq. centimeter, preferably from about 1×10¹ toabout 1×10⁴ pores per square millimeter, more preferably from about1×10² to about 3×10⁴ pores per square millimeter, and the low resistancefilter has an opening density in the range of 20 to 1,000,000 pores overan area of about one square millimeter.

The term "substantially through" with reference to the pores beingformed in the membrane or material shall mean pores which eithercompletely traverse the width of the membrane or are formed to have athin peelable layer over their exit aperture. The pores formed with apeelable layer over their exit apertures are formed so as to peeloutward at a substantially lower pressure than would be required torupture the membrane in the nonporous areas.

GENERAL OVERVIEW OF THE METHODOLOGY OF THE INVENTION

The invention provides a means to deliver any type of drug or diagnosticagent to a patient by ocular administration or inhalation in the form ofan aerosol having a desired aerosol particle size and havingsubstantially no undesirable particles within the aerosol that wouldsubstantially affect the accuracy of the dose of drug or diagnosticagent delivered in the aerosol. The method of generating an aerosolaccording to the invention provides a means to generate a reproducibledesirable dose of aerosol for therapeutic and diagnostic applications.Moreover, certain embodiments of the devices and methodology used do notrequire the release of low boiling point propellants in order toaerosolize drug, which propellants are conventionally used in connectionwith hand-held metered dose inhalers. However, like conventionalhand-held metered dose inhalers, the devices used in conjunction withthe present invention can be hand-held, self-contained, highly portabledevices which provide a convenient means of delivering drugs ordiagnostic agents to a patient via the respiratory route.

In general, an aerosol for respiratory or ocular delivery is generatedfrom a drug or diagnostic agent formulation, preferably a flowableformulation, more preferably a liquid, flowable formulation. The drug ordiagnostic agent formulation can be contained within a multidosecontainer or within a container portion of a disposable package, wherethe container of the disposable package has at least one surface that iscollapsible. The aerosol is generated by applying pressure of 50 bar orless, preferably 40 bar or less, to the collapsible container surface,thereby forcing the contents of the container through a low resistancefilter and then through a nozzle comprised of a porous membrane. Theporous membrane may be rigid or flexible. Preferably the porous membraneis flexible so that upon application of the pressure required to aerosolthe formulation (i.e., preferably 50 bar or less, more preferably 40 baror less), the nozzle's porous membrane becomes convex in shape, thusdelivering the aerosolized drug or diagnostic agent into the flow pathof the delivery device in a region beyond the flow boundary layer. Thelow resistance filter has a porosity the same as or preferably greaterthan the porosity of the porous membrane to provide for an overall flowresistance that is much lower than the flow resistance of the nozzle.The low resistance filter thus prevents particles of an undesirable sizefrom reaching the nozzle, thereby lessening clogging of the nozzle fromthe inside, and filters out such undesirable particles before theaerosol for delivery is generated, thereby avoiding delivery ofundesirable particles to the patient.

The formulations for use in the present invention can includepreservatives or bacteriostatic type compounds. However, the formulationpreferably comprises a pharmaceutically active drug (or a diagnosticagent) and pharmaceutically acceptable carrier such as water. Theformulation can be primarily or essentially composed of the drug ordiagnostic agent (i.e., without carrier) if the drug or diagnostic agentis freely flowable and can be aerosolized. Useful formulations cancomprise formulations currently approved for use with nebulizers or forinjections.

Further, the dispensing device of the present invention, which can beused to dispense a drug or diagnostic agent formulation according to themethod of the invention, preferably includes electronic and/ormechanical components which eliminate direct user actuation of drugrelease. More specifically, where the device is used in respiratorytherapy, the device preferably includes a means for measuringinspiratory flow rate and inspiratory volume and sending an electricalsignal as a result of the simultaneous measurement of both (so that drugor diagnostic agent can be released at a preprogrammed optimal point)and also preferably includes a microprocessor which is programmed toreceive, process, analyze and store the electrical signal of the meansfor measuring flow and upon receipt of signal values within appropriatelimits sending an actuation signal to the mechanical means which causesdrug (or diagnostic agent) to be extruded from the pores of the nozzle'sporous membrane. Thus, since preferred embodiments of the devices usedin connection with the present invention include a means of analyzingbreath flow and a microprocessor capable of making calculations basedthe inhalation profile, the present invention can provide a means forrepeatedly (1) dispensing and (2) delivering the same amount of the drugor diagnostic agent to a patient at each dosing event.

The nozzles of the invention preferably take the form of small pores ina thin membrane. The material used may be any material from whichsuitable pores can be formed and which does not adversely interact withother components of the delivery device, particularly with theformulation being administered. In a preferred embodiment, the materialis a flexible polymeric organic material, for example a polyether,polycarbonate, polyimide, polyether imide, polyethylene or polyester.Flexibility of the material is preferred so that the nozzle can adopt aconvex shape and protrude into the airstream upon application ofpressure, thus forming the aerosol away from the static boundary layerof air. The membrane is preferably about 10 to about 100 μm inthickness, more preferably from about 12 to about 45 μm in thickness. Apreferred material is a 25 μm thick film of polyimide. Considerationsfor the membrane material include the ease of manufacture in combinationwith the formulation container, flexibility of the membrane, and thepressure required to generate an aerosol from pores spanning a membraneof that thickness and flexibility.

Where a laser source is used to ablate the pores in the membrane, theparticular laser source used will to some extent be determined by thematerial in which the pores are to be formed. Generally, the lasersource must supply a sufficient amount of energy of a wavelength whichcan form an effective aerosolization nozzle in the material beingablated. Typically the wavelength can be from about 250 to about 360 nm.

The output of the particular laser source can be manipulated in avariety of ways prior to being applied to the material. For example, thefrequency can doubled or tripled using, for example, a lithium triboratecrystal or series of crystals using a type I process, a type II processor a combination thereof. This laser beam can be further split intomultiple beams to create multiple pores simultaneously. The beam canalso be directed through a mask or spatially filtered, and can also beexpanded prior to focusing.

One laser effective for such nozzles is a neodymium-yttrium aluminumgarnet laser. This laser is a pulsed ultraviolet wavelength light sourcewhich provides sufficiently high peak power in short pulses to permitprecise ablation in a thin material. The beam profile from this laser isradially symmetric which tends to produce radially symmetric pores.

Another laser effective for creating pores in materials such aspolyethers and polyimide is an excimer laser. This laser producesultraviolet wavelength light, similar to the Nd:YAG laser. However, thebeam is not radially symmetrical but can be projected through a mask tosimultaneously drill one or more conical or cylindrical holes.Preferably, the laser source is an excimer laser providing a wavelengthof 308 nm. The energy density used for such a laser typically rangesfrom about 525 to about 725 mJ/cm², and is preferably about 630 mJ/cm².Using such a laser on a 25 μm thick polyimide membrane, the number ofpulses is typically about 100 to about 200.

For respiratory delivery, the pores are formed so as to have an unflexedexit aperture diameter from about 0.5 to about 6 μm, preferably about1-2 μm. For ocular delivery, the pores are formed so as to have anunflexed exit aperture diameter in the range of 5 microns to 50 microns,preferably 7.5 to 25 microns. The pores can be spaced from about 10 toabout 1000 μm apart or more, but are preferably spaced from about 30 toabout 70 μm apart, most preferably about 50 μm apart. The pore spacingis determined in part by the need to prevent the aerosol from adjacentpores from adversely interfering with each other, and in part tominimize the amount of membrane used and the associated manufacturingdifficulties and costs. The pore spacing is preferably fairly uniform,with a variability in the interpore distance of preferably less thanabout 20%, more preferably less than about 10%, and most preferablyabout 2% or less (<1 μm variability for pores spaced 50 μm apart).

The pores may be roughly cylindrical or conical in shape, where"cylindrical" means that the pores pass perpendicularly through themembrane and have approximately the same diameter on each surface of andthroughout the membrane, and "conical" means that the pores are largeron one side of the membrane than on the other side, and includesinstances where the cross-section of the pores is conical, curved orwhere the diameter of the pore is reduced stepwise. Preferably, thepores are conical. When the pores are conical, the wider diameter of thecone is found on the entrance side of the pore to which the formulationis applied under pressure, while the smaller diameter of the cone isfound on the exit side of the pore from which aerosolization occurs. Forexample, for respiratory delivery, when the exit aperture of the holesis about 0.6 to about 1.5 μm in diameter, the entrance aperturepreferably has a diameter of from about 4 to about 12 μm, morepreferably from about 6 to about 12 μm. The aperture size is preferablyuniform; following the methods taught herein, the variability indiameter of each hole having a 1.25 μm aperture is no more than 0.05 μm,and for a 6 lm aperture is no more than 0.1 μm. The nozzle may beprovided as an integral part of the formulation packaging, or may beprovided separately, for example integrally with the inhalation device,or wound on a roll for disposable use.

In an alternative embodiment, the pores are incompletely formed so thata thin peelable layer remains covering the exit apertures of the pores.This peelable layer bursts outward upon forcible application of the drugformulation to the nozzle during drug delivery, permittingaerosolization of the formulation. The peelable layer of the pores isformed so as to have a breaking pressure significantly below that of theoverall membrane, and the pressure at which the layer bursts issignificantly below that applied in the normal course of drugadministration, so that the pores burst substantially uniformly andcompletely. The incompletely formed pores may be formed by applicationof a thin layer of material to the outer side of the membrane afterformation of complete pores, or by incompletely ablating holes throughthe membrane.

Any number of pores may be formed in the material comprising the nozzleapparatus. The number of nozzles is determined in part by the amount offormulation which must be delivered for a given application, andtherefore the potency and concentration of the agent being administeredmust be taken into account. Additionally, the period of time over whichthe formulation is to be administered must also be considered. In oneembodiment of the invention, the pores are formed in a 7×48 array ofpores spaced 50 μm apart. For a given pore exit diameter and formulationpressure, hole number can be adjusted to control delivery time. Forexample, if the expression N=356*d⁻⁰.667 is used, the pressure requiredfor a 1.2 second delivery time at each hole size will give robustaerosol generation.

In another embodiment, the pores are provided with elevated areassurrounding the exit aperture, so as to prevent liquid from intrudingfrom the outer surface of the membrane back into the pore and therebydisrupting aerosolization. The elevated areas may be of any shape, suchas circular or rectangular, or may be irregularly shaped. The elevatedareas can be constructed by any suitable means, for example by etchingaway portions of the outer layer of the membrane, by laser drillingprocedures which lead to sputtering of material around the pores, bymolding or casting, by deposition of material via a mask in locationswhere pores are to be formed, and the like. FIG. 2 shows an example of apore formed so as to have an elevated area via excimer laser ablationfrom the opposite side of the membrane. The formation of the elevatedarea via excimer laser ablation can be controlled by altering the pulsenumber: a minimal number of pulses used to penetrate the membrane willform an elevated area around the aperture on the opposite side of themembrane; increasing the number of pulses will then remove this elevatedarea. For example, for a 25 micron thick polyimide membrane, 120 pulsesof a 308 nm excimer laser at an energy density of 630 mJ/cm² will form apore having an elevated area, while increasing the number of pulsesabove 150 will remove the elevated area and slightly widen the poreaperture. The elevated areas may be of any suitable dimensions, butpreferably extend significantly less than the interpore distance so asto provide lower areas where fluid is sequestered. The elevated areascan be made from any suitable material, for example the materialcomprising the bulk of the membrane, or may be made from materials withdesirable properties such as hydrophobicity or solvent or drugrepellence so as to repel the drug formulation from entering the exitaperture of the pores.

LOW RESISTANCE FILTER, NOZZLE, AND CONTAINER CONFIGURATIONS:

In general, the low-resistance filter and nozzle comprised of a porousmembrane according to the invention can be used in conjunction with anycontainer suitable for containing a drug or diagnostic agent formulationof interest. The container can be, for example, a single-dose containeror a multidose container. The containers can be refillable, reusable,and/or disposable. Preferably, the container is disposable. Thecontainer can be designed for storage and delivery of a drug ordiagnostic agent that is dry, substantially dry, liquid, or in the formof a suspension. The container may be any desired size. In most casesthe size of the container is not directly related to the amount of drugor diagnostic agent being delivered in that most formulations includerelatively large amounts of excipient material, e.g., water or a salinesolution. Accordingly, a given size container could include a wide rangeof different doses by varying drug (or diagnostic agent) concentration.

The container can also be one that provides for storage of a drug ordiagnostic agent in a dry or substantially dry form until the time ofadministration, at which point, if desired, the drug or diagnostic agentcan be mixed with water or other liquid. An exemplary dual compartmentcontainer for carrying out such mixing of dry drug with liquid justprior to administration is described in copending U.S. application Ser.No. 08/549,295, filed Oct. 27, 1995, incorporated herein by referencewith respect to such containers.

In a preferred embodiment, the containers useful with the inventioncomprise a single-use, single-dose, disposable container that holds aformulation for delivery to a patient and has a collapsible wall. Inaddition, the container can be configured in the same package with aporous membrane and a low resistance filter, where the low resistancefilter is positioned between the porous membrane and a formulationcontained in the container. The container is preferably disposable aftera single use in the delivery of the formulation contained therein.

FIG. 2 is a cross-sectional view of a preferred embodiment of adisposable container 1 comprising the porous membrane of the invention.The container is shaped by a collapsible wall 2. The container 1 has anopening covered by a nozzle 302 comprised of a flexible porous membrane.The exit apertures of the pores of the nozzle are surrounded by elevatedareas 81 which prevent intrusion of fluid back into the pores. Thecontainer 1 includes an opening which leads to an open channel 6 whichchannel 6 includes an abutment (or peelable seal) 7 which is peeled openupon the application of force created by formulation 5 being forced fromthe container. A low resistance filter 301 can be positioned between theformulation 5 and the peelable seal 7. The filter 301 has a porositysuch that the presence of the filter 301 does not substantially increasethe pressure required to generate an aerosol by forcing the formulationthrough the porous membrane of the nozzle. When the abutment 7 is peeledopen, the formulation 5 flows to an area adjacent to the nozzle'sflexible porous membrane 3 and is prevented from flowing further in thechannel 6 by a nonbreakable abutment 8.

FIG. 3 is a cross-sectional view of another preferred embodiment of adisposable container 1 of the invention. The container is shaped by acollapsible wall 2. The container 2 includes an opening which leads toan open channel 6, which channel 6 includes an abutment (or peelableseal) 7 which is peeled open upon the application of force created byformulation 5 being forced from the container. The low resistance filter301 is positioned between the peelable seal 7 and the nozzle 302. Whenthe peelable seal 7 is broken, the formulation 5 flows to an areaadjacent the low resistance filter 301, through the low resistancefilter 301, if present, and out the nozzle 302 to form an aerosol. Theformulation 5 is prevented from flowing further in the channel 6 by anonbreakable abutment 8. A number of containers can be connectedtogether to form a package 46 as shown in FIG. 4. The package 46 isshown in the form of an elongated tape, but can be in any configuration(e.g., circular, square, rectangular, etc.).

FIG. 6 is a cross-sectional view of the disposable container 1 of FIG. 2in use for respiratory therapy. The wall 2 is being compressed by amechanical component such as the cam 9 shown in FIG. 9. The cam may bedriven by a motor connected to gears which turn the cam 9 to bring thecam into contact with and apply the necessary force to the collapsiblewall 2 of the container 1. The formulation 5 is forced through the lowresistance filter 301, if present, into the open channel 6 (breaking theabutment 7 shown in FIG. 2), and against and through the nozzle 302causing the porous membrane of the nozzle 302 to protrude outward into aconvex configuration as shown in FIG. 3. The cam 9 has been forcedagainst the container wall 2 after a patient 10 begins inhalation in thedirection of the arrow "I."

An exemplary method for using the aerosol delivery device 40 is asfollows. The patient 10 inhales through the mouth from a tubular channel11. The velocity of the air moving through the flow path 29 of thechannel 11 can be measured across the diameter of the channel todetermine a flow profile 12, i.e., the air flowing through the channel11 has a higher velocity further away from the inner surface of thechannel. The air velocity immediately adjacent to the inner surface ofthe channel 11 (i.e., infinitely close to the surface) is very slow(i.e., approaches zero). A flow boundary layer 13 defines a set ofpoints below which (in a direction from the channel center toward theinner surface of the channel) the flow of air is substantially below thebulk flow rate, i.e., 50% or less than the bulk flow rate.

As shown in FIG. 6, the convex shape that the flexible porous membraneof the nozzle 302 takes on during use plays an important role.Preferably, the upper surface of the flexible porous membrane of thenozzle 302 is substantially flush with (i.e., in substantially the sameplane as) the inner surface of the channel 11 to allow air to flowfreely. Thus, if the membrane of the nozzle 302 remained in place whenthe formulation 5 moved through the pores, the formulation would bereleased into the slow moving or substantially "dead air" below theboundary layer 13. However, when the formulation 5 is forced from thecontainer 1 by force applied from a source such as a motor-driven cam22, the formulation 5 presses against the flexible porous membrane ofthe nozzle 302 causing the porous membrane to convex outward beyond theplane of the resting surface of the nozzle's membrane 302 and beyond theplane of the inner surface of the channel 11. The convex upwarddistortion of the membrane of the nozzle 302 is important because itpositions the pores of the membrane beyond the boundary layer 13 (shownin FIG. 6) into faster moving air of the channel 11.

A device similar to the device 40 of FIG. 9 can be similarly used todeliver a drug to the respiratory tract by nasal delivery. For example,the mouthpiece 30 and opening 38 are suitably modified to provide fordelivery by nasal inhalation. Thus, the patient places the opening ofthe modified device into his nostril and, after inhalation, a dose ofthe drug is delivered to the respiratory tract of the patient in amanner similar to that described above.

Aerosol delivery of a drug to the eye can be accomplished using a devicesimilar to the device 40 described above, with modifications. Forexample, the device 40 shown in FIG. 9 is modified such that themouthpiece 30, opening 38, and channel are suitable for aerosol deliveryto the surface of the patient's eye. The patient positions the device sothat aerosol formulation exiting the opening 38 will contact the eye'ssurface; the channel is open at the opening end (opening 38) and ispreferably closed at the end opposite the opening end. The device mayadditionally comprise a means to maintain the device in a stableposition over the patient's eye and/or a means for detecting when thepatient's eye is open. Upon activation of the device, a cam 9 (or othermechanical component) crushes the collapsible wall 2 of the container 1.The formulation 5 is forced through the filter 301, into the openchannel 6 (breaking the abutment 7), and against and through the nozzle302, thereby generating an aerosol which is forced out of the devicethrough an opening so as to come into contact with the surface of theeye.

The device of the invention can use a low resistance filter and a porousmembrane to prevent clogging of the nozzle's porous membrane and toprevent the passage of undissolved particles or drug and/or otherundesirable particles from being delivered to the patient. In general,the formulation is released from a container, passed through at leastone low resistance filter, and then passed through a porous membrane ofa nozzle. An aerosol is formed from the drug formulation when it exitsthe pores of the porous membrane, and the aerosol is delivered to thepatient.

A low resistance filter and the nozzle can be included as components ofa disposable package that is composed of a container that serves as astorage receptacle for the drug formulation, a porous membrane, and alow resistance filter positioned between the drug formulation and thenozzle. Such packages and containers are as described above.

The low resistance filter and the nozzle can also be provided separatefrom the drug container and/or the disposable package. For example, thelow resistance filter can be provided as a single disposable filter thatcan be inserted in the proper position between the formulation in thecontainer and a nozzle, which can also be provided as a singledisposable unit. The disposable filter and disposable nozzle can beinserted prior to use and can be disposed after each use or after arecommended number of uses.

Alternatively, the low resistance filter and nozzle can be provided as aseparate ribbon or ribbons.

The formulation may be a low viscosity liquid formulation. The viscosityof the drug or diagnostic agent by itself or in combination with acarrier is not of particular importance except to note that theformulation must have characteristics such that the formulation can beforced out of openings to form an aerosol, e.g., when the formulation isforced through the flexible porous membrane it will form an aerosolpreferably having a particle size in the range of about 0.1 to 12microns for intrapulmonary delivery or in the range of 15 to 75 micronsfor ocular delivery.

AEROSOL DELIVERY DEVICES:

In general, aerosol delivery devices useful with the invention comprise(a) a device for holding a formulation-containing container, preferablya disposable container, with at least one but preferably a number ofcontainers, and (b) a mechanical mechanism for forcing the contents of acontainer (on the package) through a low resistance filter and a nozzlecomprised of a porous membrane. Where the device is used for respiratorydelivery, the device can further comprise (c) a means for controllingthe inspiratory flow profile, (d) a means for controlling the volume inwhich the drug or diagnostic agent is inhaled, (e) a switch forautomatically releasing or firing the mechanical means to release adetermined volume of aerosol and aerosol-free air when the inspiratoryflow rate and/or volume reaches a predetermined point, (f) a means forholding and moving one package after another into a drug releaseposition so that a new package is positioned in place for each releaseof drug, and (g) a source of power, e.g., spring, or conventionalbatteries or other source of electric power.

The aerosol delivery devices of the invention can also compriseadditional components such as, but not limited to, a monitor foranalyzing a patient's inspiratory flow (e.g., a flow sensor 31 as shownin FIG. 9 having tubes 35 and 36 connected to a pressure transducer 37,which tubes 35 and 36 communicate with the flow path 29 and whichpressure transducer is electrically connected to a microprocessor 26), aheating mechanism for adding energy to the air flow into which theaerosol particles are released (e.g., a heating mechanism 14 as shown inFIG. 9), means for measuring ambient temperature and humidity (e.g., ahygrometer 50 and thermometer 51 as shown in FIG. 9), screens to preventundesirable particles in the environment from entering the flow path(e.g., screens 32, 33, and 34 as shown in FIG. 9), and/or othercomponents that might enhance aerosol delivery and/or patient compliancewith an aerosol delivery regimen. The device can also comprisecomponents that provide or store information about a patient's aerosoldelivery regimen and compliance with such, the types and amounts of drugdelivered to a patient, and/or other information useful to the patientor attending physician. Devices suitable for aerosol delivery accordingto the invention (i.e., that can be adapted for use with a lowresistance filter and nozzle as described herein) are described in U.S.Pat. No. 5,544,646, issued Aug. 13, 1996; U.S. Pat. No. 5,497,763,issued Mar. 12, 1996; PCT published application WO 96/13292, publishedMay 9, 1996; and PCT published application WO 9609846, published Apr. 4,1996, each of which is incorporated herein by reference with respect tosuch aerosol delivery devices.

The methodology of the present invention can be carried out with adevice that obtains power from a plug-in source; however, the device ispreferably a self-contained, portable device that is battery powered.For example, the methodology of the invention can be carried out using aportable, hand-held, battery-powered device which uses a microprocessor(e.g, as the means for recording a characterization of the inspiratoryprofile) as per U.S. Pat. No. 5,404,871, issued Apr. 11, 1995, and U.S.Pat. No. 5,450,336, issued Sep. 12, 1995, incorporated herein byreference. The microprocessor is programmed using the criteria describedherein using the device, dosage units, and system disclosed in PCTApplication US94/05825 with modifications as described herein.Alternatively, the methodology of the invention can be carried out usinga mechanical (nonelectronic) device. Those skilled in the art wouldrecognize that various components can be mechanically set to actuate ata given inspiratory flow rate and at a given volume (e.g., a spinnableflywheel which rotates a given amount per a given volume).

An exemplary device 40 of the invention is shown in FIG. 9. The device40 is a hand held, self-contained, portable, breath-actuated inhalerdevice 40 having a holder 20 with cylindrical side walls and a hand grip21. The holder 20 is "loaded," i.e., connected to a container 1 thatincludes dosage units having liquid, flowable formulations ofpharmaceutically active drug or diagnostic agent therein. A plurality ofcontainers 1 (2 or more) are preferably linked together to form apackage 46. FIG. 10 is a cross-sectional view of a cassette 500 loadedinto a delivery device 40. The disposable package 46 (as depicted inFIG. 9) is folded or wound into the cassette 500 in a manner which makesit possible to move the individual containers 1 into a formulationrelease position within the device 40. While the containers 1 are movedinto position the cover 400 is removed. Although it is possible torewind any used portion of the package on a sprocket 70 and rewind theused cover 400 on a sprocket 80 or randomly fold it into a compartment,it is also possible to dispense the used portion outside of the cassette500 and device 40 and immediately dispose of such.

It is to be understood that while the invention has been described inconjunction with the preferred specific embodiments thereof, that theforegoing description as well as the examples which follow are intendedto illustrate and not limit the scope of the invention. Other aspects,advantages and modifications within the scope of the invention will beapparent to those skilled in the art to which the invention pertains.

All patents, patent applications, and publications mentioned herein arehereby incorporated by reference in their entirety.

EXAMPLES Example 1

PREPARATION OF NOZZLES

Nozzles were prepared from thin-film polyimide (25 μm, Kapton™ Type100H, DuPont) using a laser (Uniphase, model s355B-100Q). The film washeld by a vacuum platen to a three axis stage.

To determine the effect of power level and number of pulses on poresize, the power and pulse number was varied in a systematic fashion aspores were drilled in a single piece of Kapton. A second orderpolynomial fit of the pore size vs. power level was performed, and wasused to estimate the power required to drill pores of diameter 1, 1.5,and 2 μm. Sample nozzles were fabricated at various power levels, andpores on each sample were sized, and the average size computed. Thisprocess was iterated until a power level was determined that gave anaverage pore size within 5% of the desired value.

                  TABLE I                                                         ______________________________________                                        Power Level vs Pore Size                                                      Desired Pore Size                                                                            Power Level Used                                               ______________________________________                                        1.0 μm      1.1 mW                                                         1.5 μm      1.5 mW                                                         2.0 μm      1.9 mW                                                         ______________________________________                                    

Nozzles for the experiments below were fabricated at these settings. Thepower was checked and adjusted after every 10 nozzles.

To determine pore size, nozzles were imaged using a scanning electronmicroscope (Philips, model 505). The samples were coated by golddeposition (Denton Desk II, 45 μA, 120 seconds) prior to imaging. Theimages were digitized at video resolution using a frame grabber (DataTranslation DT3152). Video frames (64) were averaged to create a finalimage, which was stored to disk. After 10 images had been acquired inthis manner, they were read into an image processing software package(Optimus, version 6.0). A macro was developed that determined theperimeter of the pores by thresholding, and based on this perimeter, anarea equivalent diameter was calculated. The area equivalent diameterdetermined for the 10 pores was averaged to determine the finaldiameter.

Example 2

Nozzles prepared as described in Example 1 were tested for generatedMMAD (median size of generated aerosol), σ_(g) (dispersion of thegenerated aerosol size distribution), and emitted dose. The nozzles wereapplied to AER_(x) system disposable packages, as described in U.S. Pat.No. 5,544,646 (incorporated herein by reference), and loaded into anAER_(x) inhaler. Nominal values for the experiment were airflow=70liters per minute.

The MMAD of the particles prior to evaporation was measured by phaseDoppler particle sizing (Aerometrics, RSA, XMT 1145, RCV 2100). PhaseDoppler particle sizing uses a laser beam to scatter light fromspherical aerosol particles. The scattered light is detected andanalyzed to determine the particle size and velocity distribution.

The Aerometrics system was first calibrated using polystyrene latexmicrospheres (Duke Scientific 4205A). The particles were suspended inwater, launched with a jet nebulizer (Hudson RCI, UpDraft II), and driedprior to introducing them into the probe volume. After calibration, thetest aerosol was launched using an AER_(x) system. The edge of the clampwas placed about 1.5" from the probe volume, with the plume centered onthe probe volume, using nozzles of the sizes prepared in Example 1. Theindex of refraction used for calculations was 1.33.

Emitted dose was measured by collecting the aerosol from a singleadministration onto a 47 mm glass fiber filter (61631, Gelman Sciences).The aerosol was drawn from the AER_(x) system into a tapered sectionwhich fit tightly into a 90° glass twin impinger throat (Erweka Corp.,part no. 007-04), attached to the filter holder.

We found emitted doses of about 65% or greater are obtained by usingpores of 1 μm diameter, using a 1.2 second extrusion time. Four of theruns (7%) exceeded 80% emitted dose, and 20 runs (37%) exceeded 60%emitted dose.

The measured MMAD ranged from 8.70 μm to 4.37 μm, while σ_(g) wasessentially constant over the experimental range.

Example 3

Purpose:

To determine the effect of variable exit hole size on the emitted doseand aerosol quality obtained with Excimer Nozzles.

The nozzle lots used in this experiment were designed to have exit holesizes of approximately 0.8-1.5 μM.

ED, MMAD, GSD and FPD results were measured.

ED--fraction of the loaded dose that is emitted from the device

MMAD--mass median aerodynamic diameter

GSD--geometric standard deviation

FPD--fine particle dose (fraction of the dose loaded in the jacket thatexits the mouthpiece in particles<3.5 μM aerodynamic diameter

Packet Preparation: the nozzles were drilled using a UV excimer laser.After scanning electron microscopy (SEM) to examine a portion of thenozzles, the remaining nozzle file was sealed to blister jackets. Thetest liquid was 45 μl of cromolyn sodium (30 mg/ml) aqueous solution.

    ______________________________________                                        SUMMARY PERFORMANCE DATA                                                      SEM exit hole size (μm)                                                    from different sub-lots                                                                    ED (%)      MMAD (μm)                                                                             GSD                                       ______________________________________                                        1.32 ± 0.05                                                                             72.3 ± 3.9                                                                             2.51       1.48                                      1.45 ± 0.08                                                                1.20 ± 0.1                                                                              68.2 ± 1.5                                                                             2.68       1.44                                      1.38 ± 0.05                                                                1.40 ± 0.05                                                                             73.4 ± 6.1                                                                             2.60       1.41                                      0.51 ± 0.13                                                                             67.13 ± 6.95                                                                           1.67       1.39                                      0.81 ± 0.09                                                                             72.04 ± 2.72                                                                           2.38       1.41                                      0.82 ± 0.16                                                                             75.96 ± 6.9                                                                            2.20       1.44                                      ______________________________________                                    

FIG. 12 shows that MMAD increases with hole size as expected.

What is claimed is:
 1. A nozzle for aerosolizing a drug formulation,comprising:a sheet of flexible membrane material having a nozzle areawhich area has a plurality of pores therein wherein the pores have anunflexed exit aperture diameter in the range of about 0.5 to about 50microns which pores are positioned at a distance in the range of about30 to about 70 microns apart from each other.
 2. The nozzle of claim 1,wherein the pores are formed so that a layer of material covers the exitaperture, wherein said pores bursts outward upon application of apressure that does not otherwise rupture the nozzle.
 3. The nozzle ofclaim 1, wherein the exit aperture of said pores is surrounded by anelevated area.
 4. The nozzle of claim 3, further comprising:a removablecover sheet connected to the sheet of membrane material, the cover sheetbeing attached in a manner which covers at least the area with porestherein.
 5. The nozzle of claim 3, wherein the flexible membranematerial has a thickness in the range of about 15 to 40 microns.
 6. Thenozzle of claim 5, wherein the flexible membrane material thickness isin the range of about 20 to 30 microns.
 7. The nozzle of claim 6,wherein the flexible membrane material thickness is about 25 microns. 8.The nozzle of claim 3, wherein the nozzle area with pores therein has100 or more pores.
 9. The nozzle of claim 8, wherein the nozzle areawith pores therein has 200 or more pores.
 10. The nozzle of claim 3,wherein the pores are regularly spaced in the area in rows.
 11. Thenozzle of claim 3, wherein the flexible membrane material is a polymerselected from the group consisting of polyimides, polyether imides,polyethers, polyesters, polyethylene and polycarbonates.
 12. The nozzleof claim 3, wherein the pores are conical.
 13. The nozzle of claim 3,wherein said nozzle comprises a plurality of nozzle areas.
 14. A methodof generating an aerosol, comprising forcibly applying a flowable liquidformulation to the nozzle of claim
 3. 15. A method of delivering a drugor diagnostic agent to an individual, comprising:forcibly applying aliquid comprising the drug or diagnostic agent to the nozzle of claim 2so that an aerosol containing the drug or diagnostic agent is generated;and administering the aerosol to an area of the individual in apharmaceutically acceptable and effective manner.
 16. A disposablepackage for use in aerosolized delivery of drugs to the lung,comprising:a container having at least one wall which is collapsible bythe application of a force and having at least one opening; and a nozzlecovering the opening of the container, wherein the nozzle is comprisedof a sheet of flexible membrane material having a nozzle area which areahas a plurality of pores therein, wherein the pores have an unflexedexit aperture diameter in the range of about 0.5 to 50 micron whichpores are positioned at a distance in the range of about 30 to 70microns apart from each other.
 17. The disposable package of claim 16,wherein the opening leads to an open channel and the nozzle ispositioned at the end of the open channel.
 18. The package of claim 17,wherein a filter is positioned in the open channel.
 19. A disposablepackage for use in aerosolized delivery of material to a lung,comprising:a container having at least one wall which is reversiblycollapsible by the application of force and having at least one opening;and a porous membrane covering the opening wherein the membrane poreshave an unflexed exit aperture diameter in a range of about 0.5 to about5.0 microns, and wherein the pores are configured to have an elevatedarea surrounding the exit aperture of the pore.
 20. The disposablepackage of claim 19, wherein the elevated areas are formed as anintegral part of the membrane as elevated areas on the membrane prior toforming pores at the center of the elevated areas.
 21. The disposablepackage of claim 19, wherein the elevated areas are formed by a thinmembrane layer at an end of a partially formed pore which thin membranelayer is broken as material is forced out.
 22. The disposable package ofclaim 19, wherein the elevated areas are formed by depositing elevatedareas on the membrane and making pores in the membrane through theelevated areas.
 23. The disposable package of claim 19, wherein theelevated areas are formed by etching away surrounding areas to leaveelevated areas on the member and making pores through the elevatedareas.
 24. A disposable package for use in aerosolized delivery ofmaterial to lungs, comprising:a container having at least one wall whichis collapsible by the application of force and having at least oneopening, the container having therein a liquid, flowable formulation;and a membrane covering the opening wherein the membrane comprises aplurality of substantially circular weakened areas having an unflexeddiameter in a range of about 0.5 to about 5.0 microns which weakenedareas burst when pressure is applied while the remainder of the membraneremains unbroken.